Gene editing can help treat congenital disease before birth

Prenatal treatment could open a door to disease prevention, for HT1 and potentially for other congenital disorders.

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New York: In a first, a team of scientists have performed prenatal gene editing to prevent a lethal metabolic disorder in laboratory mice, offering the potential to treat human congenital diseases before birth. The study led by research from Children's Hospital of Philadelphia (CHOP) and the University of Pennsylvania used both CRISPR-Cas9 and base editor 3 (BE3) gene-editing tools and reduced cholesterol levels in healthy mice treated in utero by targeting a gene that regulates those levels.

They also used prenatal gene editing to improve liver function and prevent neonatal death in a subgroup of mice that had been engineered with a mutation causing the lethal liver disease hereditary tyrosinemia type 1 (HT1).

HT1 in humans usually appears during infancy, and it is often treatable with a medicine called nitisinone and a strict diet. However, when treatments fail, patients are at risk of liver failure or liver cancer. Prenatal treatment could open a door to disease prevention, for HT1 and potentially for other congenital disorders.

"Our ultimate goal is to translate the approach used in these proof-of-concept studies to treat severe diseases diagnosed early in pregnancy," said William H. Peranteau, a paediatric and foetal surgeon at CHOP.

"We hope to broaden this strategy to intervene prenatally in congenital diseases that currently have no effective treatment for most patients, and result in death or severe complications in infants," he added. In the study, published in the journal Nature Medicine, the team used BE3, joined it with a modified CRISPR-associated protein 9.

After birth, the mice carried stable amounts of edited liver cells for up to three months after the prenatal treatment, with no evidence of unwanted, off-target editing at other DNA sites. In the subgroup of the mice bio-engineered to model HT1, BE3 improved liver function and preserved survival.

However, "a significant amount of work needs to be done before prenatal gene editing can be translated to the clinic, including investigations into more clinically relevant delivery mechanisms and ensuring the safety of this approach", said Peranteau.

He added: "Nonetheless, we are excited about the potential of this approach to treat genetic diseases of the liver and other organs for which few therapeutic options exist."